Protecting the malaria drug arsenal: halting the rise and spread of amodiaquine resistance by monitoring the PfCRT SVMNT type

Abstract

The loss of chloroquine due to selection and spread of drug resistant Plasmodium falciparum parasites has greatly impacted malaria control, especially in highly endemic areas of Africa. Since chloroquine removal a decade ago, the guidelines to treat falciparum malaria suggest combination therapies, preferentially with an artemisinin derivative. One of the recommended partner drugs is amodiaquine, a pro-drug that relies on its active metabolite monodesethylamodiaquine, and is still effective in areas of Africa, but not in regions of South America. Genetic studies on P. falciparum parasites have shown that different pfcrt mutant haplotypes are linked to distinct levels of chloroquine and amodiaquine responses. The pfcrt haplotype SVMNT (termed after the amino acids from codon positions 72-76) is stably present in several areas where amodiaquine was introduced and widely used. Parasites with this haplotype are highly resistant to monodesethylamodiaquine and also resistant to chloroquine. The presence of this haplotype in Africa was found for the first time in 2004 in Tanzania and a role for amodiaquine in the selection of this haplotype was suggested. This commentary discusses the finding of a second site in Africa with high incidence of this haplotype. The >50% SVMNT haplotype prevalence in Angola represents a threat to the rise and spread of amodiaquine resistance. It is paramount to monitor pfcrt haplotypes in every country currently using amodiaquine and to re-evaluate current combination therapies in areas where SVMNT type parasites are prevalent.

Various pfcrt and pfmdr1 Genotypes of Plasmodium falciparum Cocirculate with P. malariae, P. ovale spp., and P. vivax in Northern Angola

“…The pfcrt SVMNT haplotype is associated with AQ resistance; it is postulated to carry a lower fitness cost than the CVIET haplotype and to persist among the parasite population even after the removal of drug pressure, potentially jeopardizing the effectiveness of artesunate-AQ, which is widely used in west Africa (37,38). Surprisingly, this haplotype, which is usually found in South America and parts of Asia, was detected in adult samples from Luanda in 2007 (15).…”

“…The different pfcrt mutant haplotypes have a consistent geographical distribution: the CQR haplotype CVIET is predominant in southeast Asia and Africa, whereas the AQ-resistant (AQR) haplotype SagtVMNT is predominant in Asia and South America, and StctVMNT, from South America, is very rare in Africa (16).The wild-type haplotype CVMNK is widespread (6,16,29,38). A recent study reported the presence of the StctVMNT haplotype of pfcrt in Angola, but this has not yet been verified by others (15,37). Polymorphisms in the parasite protein Pgh-1, encoded by pfmdr1, are thought to modulate resistance to drugs such as quinine, mefloquine, halofantrine, artemisinin, lumefantrine, CQ, and AQ (1,21,32,38).…”

A Cross-Sectional Survey of Plasmodium falciparum pfcrt Mutant Haplotypes in the Democratic Republic of Congo

“…7 Recent data confirm the appearance in neighboring Tanzania 8 and Angola 9 of the pfcrt haplotype SVMNT, which may confer resistance to amodiaquine 1,10 and herald failures of ASAQ. 11 Additionally, the haplotype SVIET has been reported from Kinshasa in 2000, although it is of unclear biological significance. 12 To inform current and future guidelines on antimalarial use in Central Africa, we conducted a cross-sectional survey of pfcrt haplotypes in the DRC.…”

Different Patterns of pfcrt and pfmdr1 Polymorphisms in P. falciparum Isolates from Nigeria and Brazil: The Potential Role of Antimalarial Drug Selection Pressure

“…19 Parasites with the SVMNT haplotype are highly resistant to MDAQ, but only moderately resistant to CQ, whereas P. falciparum clones with the CVIET haplotype are moderately resistant to MDAQ and highly resistant to CQ. These data, coupled with observations on the historical use of AQ in India, Brazil, and other malaria-endemic areas of the Americas and South Pacific suggest that AQ had an early and prominent role in the selection of drug-resistant SVMNTtype parasites 20 ; it is not clear through which mechanism the different pfcrt haplotypes interact with AQ, MDAQ, or CQ.…”